Pearls and Pitfalls The Diagnosis of Food Allergy

Food allergies can result in life-threatening reactions and diminish quality of life. In the last several decades, the prevalence of food allergies has increased in several regions throughout the world. Although more than 170 foods have been identified as being potentially allergenic, a minority of these foods cause the majority of reactions, and common food allergens vary between geographic regions.  Developments in food allergy diagnostics with regard to the verification of specific IgE antibodies and the identification of the responsible allergens. Results of IgE-binding tests with food extracts are hampered by cross-reactive proteins, low-quality test agents, or both. Specificity can be increased by defining adequate cutoff values, whereas sensitivity can be improved by using high-quality test agents. IgE-binding tests with purified allergens enabled reliable quantification of allergen-specific IgE titers, with higher levels found in individuals with food allergy compared with individuals without food allergy. However, the overlap in individual test reactivity between allergic and nonallergic subjects complicates interpretation. Recombinant allergens and synthetic sequential epitopes enabled detection of sensitization profiles, with IgE specific to several allergens and substructures now being suggested as markers of severity, persistence, or both. However, high-power quantitative studies with larger numbers of patients are required to confirm these markers. IgE-binding tests merely indicate sensitization, whereas the final proof of clinical relevance still relies on family/case history, physical examinations, and provocation tests. Novel technologies promise superior diagnostics. Microarray technology permits simultaneous measurement of multiple IgE reactivities regarding specificity, abundance, reactivity, or interaction. Improved functional tests might enable reliable estimation of the clinical relevance of IgE sensitizations at justifiable expenses.

The evaluation requires a thorough history and physical examination to consider a broad differential diagnosis, to ascertain possible trigger foods, and to determine a likely general pathophysiologic basis, specifically whether the food-induced allergic disorder is likely IgE mediated, which guides testing. The history should determine the possible causal food or foods, quantity ingested, time course of reaction, ancillary factors (exercise, aspirin, and alcohol), and reaction consistency. The history also focuses on details that might contribute to estimating the prior probability of an allergic reaction to a specific food. For example, reasoning dictates that a food ingested infrequently is more likely responsible for an acute reaction than one previously tolerated; that contamination of a meal by a previously diagnosed allergen should be considered ahead of a less likely explanation, such as development of a new allergy to a previously tolerated food; and that major allergens are inherently more likely to be triggers than other foods. To arrive at a diagnosis, the clinician should consider the epidemiologic aspects of the disease (eg, common triggers and common associations) and the details of the specific history and then consider appropriate testing that can be evaluated in the context of these prior probability estimates.

Accurate diagnosis of food allergy and appropriate treatment options depend on the verification of functionally relevant, allergen-specific IgE antibodies (sIgEs), as well as on the identification of the responsible allergenic molecule or molecules. Today, a variety of in vivo and in vitro test systems are available to investigate sIgEs as biomarkers for allergy specification. However, a positive sIgE test result merely identifies sensitization to a particular allergen and does not permit definitive differentiation between clinically relevant IgE reactivity (ie, reactivity that is capable to cross-link FcεRI receptors) and IgE reactivity not accompanied by clinical symptoms (ie, reactivity without an effector cell response). As a consequence, the clinical interpretation of sIgE test results with food extracts is often impeded by clinically irrelevant food-food or pollen-food cross-reactive IgE antibodies, leading to positive test results in subjects without clinical food allergy. A further problem is that commercially available food extracts are often not standardized, and the content of functional allergenic molecules varies based on the nature and quality of the food, the extraction procedure, and storage conditions.

Double-blind, placebo-controlled food challenges overcome the problem of determining the clinical relevance of sIgE reactivity, which is why they are still the gold standard in food allergy diagnostics, against which all other approaches should be verified. However, in vivo provocation tests with food allergens carry the risk of inducing severe allergic reactions. Therefore functional sIgE tests to detect basophil activation in vitro by using either patients’ cells directly or serum IgE coated to a basophil cell line have been suggested as surrogates.

Progress in biochemistry and molecular biology allowed for the identification, cloning, and recombinant production of allergenic proteins, as well as the synthesis of IgE epitope–emulating peptides of a number of food allergens. These new measures enabled component-resolved diagnostics of food allergy by detecting and quantifying IgE antibodies specific to a protein or even a sequential epitope. Component-resolved diagnosis revealed individual sensitization patterns to (1) different proteins of an allergenic food, (2) homologous proteins in different foods, and (3) different epitopes of a single allergenic molecule. Nevertheless, cumulative analyses of these results also revealed the presence of common sensitization patterns to major allergenic molecules of a single food, as well as to immunodominant IgE epitopes in a single allergenic molecule. These findings encourage the use of panels of purified native or recombinant allergenic molecules and the use of synthetic sequential epitopes for an elaborate molecular analysis of sensitization patterns. This promises refined diagnosis, risk assessment, and prediction in food allergy. The present review aims at providing a general conspectus on the basis and current effect of diagnostic IgE-binding tests with recombinant food allergens or the respective sequential epitopes.

For IgE-mediated disorders, skin prick tests (SPTs) provide a rapid means to detect sensitization. Negative SPT responses essentially confirm the absence of IgE-mediated allergic reactivity (negative predictive accuracy, >90%). However, a positive test response does not necessarily prove that the food is causal (specificity, <100%). Consideration of the clinical history and disease pathophysiology is required to maximize the utility of test results. For example, a positive SPT response can be considered confirmatory when combined with a recent clear history of a food-induced allergic reaction to the tested food. Additionally, increasing SPT wheal size is correlated with an increasing likelihood of clinical allergy. Studies have attempted to define wheal sizes above which allergy is virtually confirmed based on the test result alone however, these studies have been limited to a few foods in infants using specific techniques in only a few populations. In one study of 140 children evaluated for peanut allergy, 64 had positive SPT responses, and 18 reacted during oral peanut challenge. Of 17 children with an SPT wheal of greater than 10mm, only 8 reacted during the challenge. Thus additional studies are needed to continue to define the diagnostic accuracy of skin test wheal sizes for different foods, ages, disease, and populations; wheal size has not been correlated to severity of outcomes. When evaluating allergy to many fruits and vegetables, commercially prepared extracts are often inadequate because of the lability of the responsible allergen, and therefore the fresh food might be used for testing.

Serum immunoassays to determine food-specific IgE antibodies (the term RAST is now antiquated) provide another modality to evaluate IgE-mediated food allergy. Increasingly higher concentrations of food-specific IgE levels correlate with an increasing likelihood of a clinical reaction but do not generally correlate very well with reaction severity. Different predictive values are being generated from emerging studies, which might represent nuances of diet, age, disease, and challenge protocols. Particular values associated with a high likelihood of clinical allergy (eg, >95%) are often referred to as diagnostic values. Undetectable serum food-specific IgE might be associated with clinical reactions for 10% to 25%. Consequently, if there is a suspicion of possible allergic reactivity, a negative SPT response, negative physician-supervised food challenge result, or both are necessary to confirm the absence of clinical allergy. Nomograms are available where prior probabilities can be used along with likelihood ratios (determined from studies evaluating the diagnostic utility of tests) to predict a diagnosis; however, there are few studies providing likelihood ratios, and results vary. A decrease in specific IgE concentration is associated with an increasing chance of allergy resolution. A complete primer of food allergy diagnosis is beyond the scope of this review, but provides additional insights and information that are key to accurate diagnostics.

Pearls and pitfalls regarding the diagnosis of food allergy

Pearl/observation
Additional details
Clinical application
A positive skin test or serum food-specific IgE test result indicates sensitization but not necessarily clinical allergy
Screening with indiscriminate panels of tests is poorly informative
The history and epidemiologic considerations should guide test selection Tolerated foods generally need not be tested Differential diagnosis should include alternative allergen triggers (environmental aeroallergens) and nonallergic diseases (eg, intolerance)
Dose, manner of preparation, and ancillary (eliciting) factors might alter reaction outcomes
Alcohol, NSAIDs, and exercise are among eliciting factors that might facilitate a reaction Heating can alter allergenicity (eg, bakery products with egg/milk might be tolerated when whole forms are not, and cooked fruits might be tolerated when raw fruits are not) A low dose might be tolerated, whereas larger amounts might not
The history should focus on amounts triggering a reaction and ancillary factors The history should explore the types of foods tolerated or not tolerated
IgE binding to homologous proteins among food groups and between foods and pollens might have variable clinical relevance
Rates of clinical cross reactivity:
Care should be used in not overtesting For some categories and foods, avoidance of the entire group might be prudent, especially to avoid cross-contact in preparation, but individualization might be possible
Allergy to: Related food Approximate clinical reaction rate
Peanut Most beans 5%
A tree nut Other tree nut 35% Higher for: walnut-pecan, almond-hazel, cashew-pistachio
A fish Other fish 50%
Shellfish Another shellfish 75%
Grain Another grain 20%
Cow’s milk Goat/sheep milk Mare’s milk Beef >90% 5% 10%
Tests for serum food-specific IgE might not provide comparable results among manufacturers
In the United States there are 3 major test manufacturers
Care must be taken in evaluating test results over time when different manufacturers are used
Serum/skin tests might be negative despite clinical reactivity
Might be due to reagent lacking relevant protein Might be because reaction is not IgE mediated
Do not discount a convincing history because of a negative test result Consider testing with fresh food (prick-prick test) Be cognizant of non–IgE-mediated allergic reactions
Increasingly high serum food-specific IgE levels or increasingly larger skin test wheal sizes indicate greater chances of clinical allergy
Correlation of tests with outcomes vary by centers, age, and disease (equivalent results are generally more predictive of allergy in a younger patient) Results are not strongly reflective of severity
Tests should not be viewed solely as positive/negative Results can be followed over time to monitor allergy persistence/resolution Specific correlative values might not be applicable over all patient groups
At specific high levels of IgE or large skin tests, clinical reactivity is highly likely; however, studies are limited, and variations in diagnostic cutoff values are reported
Food
Mean age 5 y, 50% react
Mean age 5 y, ∼95% react
Age <2 y, ∼95% react
Egg (kUa/L)
2
7
2
Milk (kUa/L)
2
15
5
Peanut (kUa/L)
2/5 14

Diagnosis of food allergy with synthetic sequential epitopes

Today, the stability of class I food allergens is generally believed to be responsible for their capacity to provoke severe systemic reactions. They have the potential to retain IgE reactivity even after digestion, probably because of sequential IgE epitopes, whereas in class II food allergens a single point mutation can result in an almost complete loss of IgE reactivity based on the disruption of the tertiary structure. Studies on conformational IgE epitopes are rare because the investigation of discontinuous epitopes is far more challenging than the investigation of sequential epitopes. The latter are detectable by means of epitope mapping with captured overlapping synthetic peptides that represent the entire amino acid sequence of the respective allergen. However, this technology has critical limitations. Most importantly, it allows a maximum peptide length of 15 amino acids because of less than 100% efficiency of the coupling reaction. Using 10 to 15 mers at shifting offsets of 1 to 7 amino acids, several patient-specific, as well as immunodominant, epitopes were identified in different class I food allergens. However, other studies at different shifting offsets, with different peptides sizes, or both revealed different sets of immunodominant sequential epitopes for the same allergens.

Nevertheless, approaches to use these alleged immunodominant peptides for the risk assessment of life-threatening symptoms, as well as the prediction of persistence in food hypersensitivity, were apparently successful. In wheat-dependent exercise-induced anaphylaxis, all sera from affected patients showed significant sIgE reactivity to the respective peptides, whereas none of the sera from nonatopic control subjects demonstrated reactivity, and sera from control patients with atopic dermatitis showed very low to nonexistent reactivity. The sera of individuals with a history of more severe peanut-induced allergic reactions recognized a higher number of sequential Ara h 1, Ara h 2, and Ara h 3 epitopes than sera from individuals with milder symptoms. However, a higher number of recognized epitopes was also correlated with larger sIgE polyclonality.Furthermore, it could be demonstrated that sera of patients with persistent food allergy recognized specific sequential epitopes and showed significantly higher peptide-specific IgE titers than sera of patients who subsequently gained tolerance

Individual patterns in sequential epitope binding were variable, and a significant overlap in individual test reactivity between severely affected subjects and patients with milder symptoms was also evident.

In conclusion, risk assessment and prediction of permanence appears to be attainable in class I food allergy by using sequential epitope-emulating peptides. However, the detection of different immunodominant sequential epitopes in the same allergenic protein, depending on the design of the study, demands definite explanation. Additional high-power studies with quantitative approaches in a larger number of patients are requested to confirm the advantages of sequential peptides with respect to differentiating diagnostics in food allergy

Benefits and problems of allergen preparations used for in vitrodiagnostics

Natural extracts Native allergens Recombinant proteins
Benefits
Easy to prepare
Ideally, all allergenic proteins are present
Enabling of component-resolved diagnosis
Native protein structures are mostly preserved
Presence of all natural isoforms and posttranslational modifications
Enabling of component-resolved diagnosis and application of a single isoform
Lack of impurities with other food proteins
Standardization of amount and structural characteristics
Problems
Standardization problems caused by the natural variability of active ingredients (eg, various isoforms with different IgE-binding capacities) and endogenous degradation that also can cause low assay sensitivity
Complex mixtures of allergenic and nonallergenic components sometimes resulting in low assay specificity
Laborious preparation
Yield depends on composition of source material
Risk of variable batch composition caused by different copurification yields of isoforms
Risk of low-level contamination with other allergens from the same source and purification artifacts
Laborious preparation
Proteins can be unfolded or partially unfolded and might not be properly modified after translation
Risk of low-level contamination with components of the expression system and purification artifacts

Diagnosis of IgE-mediated food allergy

Medical history and physical examination

Guideline 2:The EP recommends using medical history and physical examination to aid in the diagnosis of FA.

  • Medical history: The EP recommends using a detailed medical history to help focus the evaluation of an FA. Although the medical history often provides evidence for the type of food-induced allergic reaction and the potential causative food(s) involved, history alone cannot be considered diagnostic of FA.
  • Physical examination: The EP recommends performing a focused physical examination of the patient, which may provide signs consistent with an allergic reaction or disorder often associated with FA. However, by itself, the physical examination cannot be considered diagnostic of FA.
  • Rationale: Medical history is useful for identifying food allergens that may be responsible for IgE-mediated allergic reactions, but it lacks sufficient sensitivity and specificity to definitively make a diagnosis of FA. Moreover, medical history is more useful in diagnosing immediate food-induced allergic reactions compared with delayed reactions. Further evaluation, for example laboratory studies or oral food challenges, is required to confirm a diagnosis of FA.
  • Balance of benefits and harms: The medical history and physical examination provide evidence for suspecting FA and focus the evaluation. However, basing the diagnosis of FA on either history or physical examination alone may lead to an erroneous diagnosis of FA and unnecessarily restrictive diets that could have adverse nutritional and social consequences.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • In evaluating a patient with suspected FA, a thorough medical history is very important in identifying symptoms associated with FA and focusing the diagnostic workup, but alone cannot be considered diagnostic. The nature of the reaction often suggests the underlying mechanism, either IgE mediated (immediate) or non-IgE mediated (delayed), and will determine the diagnostic tests to be used. Because none of the symptoms of FA are pathognomonic for the disorder, the medical history may be used to help identify causative allergens or to differentiate the reaction from nonallergic disorders, even though history alone does not provide sufficient sensitivity or specificity to make a diagnosis of FA.
  • Critical questions should include the following:
•What are the symptoms of concern?
•What food precipitates the symptoms, and has this food caused such symptoms more than once?
•What quantity of food was ingested when the symptoms occurred?
•Was the food in a baked (extensively heated) or uncooked form?
•When did symptoms occur in relation to exposure to a given food?
•Can the food ever be eaten without these symptoms occurring?
•Were other factors involved, such as exercise, alcohol, or use of aspirin or NSAIDs?
•Have the symptoms been present at times other than after exposure to a given food?
•What treatment was given, and how long did the symptoms last?

No findings in a physical examination are diagnostic of FA. The presence of physical signs at the time of the physical examination may verify the diagnosis of an atopic disorder (for example, urticaria or AD) or suggest prolonged symptoms (for example, loss of body weight in patients with EoE). Physical examination also may reveal findings more suggestive of a nonallergic disorder that would require further investigation and testing.

Guideline 3: The EP recommends that parent and patient reports of FA must be confirmed, because multiple studies demonstrate that 50% to 90% of presumed FAs are not allergies.

  • Rationale: Given the low positive predictive value of self-reported symptoms, it is important that all suspected FA be confirmed by appropriate evaluation (for example, oral food challenge or tests for allergic sensitization).
  • Balance of benefits and harms: Because unnecessary food avoidance affects quality of life and nutrition, there is possible harm in over-diagnosing FA.
  • Quality of evidence: High
  • Contribution of expert opinion: Minimal
  •  2 systematic reviews/meta-analyses found that the prevalence of FA based on self-reported symptoms of FA was several-fold higher compared with when the diagnosis was based on sensitization alone, sensitization with symptoms, or DBPCFC.

Methods to identify the causative food

When evaluating a patient for FA, the diagnostic tests selected are based on a comprehensive medical history. The history should suggest the possible allergic mechanism involved (ie, IgE mediated or non-IgE mediated), which then determines the types of testing to be pursued and the possible foods involved. Tests selected to evaluate FA should be based on the patient’s medical history and not comprise large general panels of food allergens. In addition, diagnostic tests for nonallergic disorders may be needed, depending on the differential diagnosis.

Skin prick test

  • Guideline 4: The EP recommends performing an SPT (also known as a skin puncture test) to assist in the identification of foods that may be provoking IgE-mediated food-induced allergic reactions, but the SPT alone cannot be considered diagnostic of FA.
  • Rationale: SPTs are safe and useful for identifying foods potentially provoking IgE-mediated food-induced allergic reactions, but they have a low positive predictive value for the clinical diagnosis of FA.
  • Balance of benefits and harms: The reagents and methods for performing SPTs are not standardized. Nevertheless, SPTs effectively detect the presence of sIgE, but many patients have sIgE without clinical FA. Compared with oral food challenges, SPTs have low specificity and low positive predictive value for making an initial diagnosis of FA. Thus, use of SPTs in the clinical setting may lead to over-diagnosis. However, in a patient with confirmed FA, an SPT is valuable in identifying the food(s) responsible for IgE-mediated FA. In the clinical setting, when compared with oral food challenges, SPTs have high sensitivity and high negative predictive values.
  • Quality of evidence: Moderate
  • Contribution of expert opinion: Significant
  • The results of an SPT are considered “immediate” because the wheal and flare develop typically within 30 minutes following injection of allergen. SPTs are the most commonly performed procedure in the evaluation of IgE-mediated FA.However, there are no standard reagents for SPT testing, and no international standards for administering the test and interpreting the results.
  • A positive SPT is generally considered a wheal with a mean diameter 3 mm or greater than the negative control. Various studies use different methods to define a positive test, from measuring the absolute wheal size to measuring the wheal size relative to the negative (diluent) and positive (histamine) controls. A positive SPT simply correlates with the presence of sIgE bound to the surface of cutaneous mast cells. Although the larger the mean wheal diameter provoked, the more likely that a food allergen will be of clinical relevance, the SPT alone is not diagnostic of FA.
  • When diagnosing OAS, or in cases where SPTs with commercial extracts do not correlate with clinical histories, the SPT technique with fresh or native foods, especially fruits and vegetables, may prove more sensitive.
  • Negative SPTs occasionally occur in patients with IgE-mediated FA. Therefore, in cases where the history is highly suggestive, further evaluation (for example, physician-supervised oral food challenge) is necessary before telling a patient that he or she is not allergic to a suspected food and may ingest it.

Intradermal tests

  • Guideline 5: The EP recommends that intradermal testing should not be used to make a diagnosis of FA.
  • Rationale: Insufficient evidence exists to support the use of intradermal testing for the diagnosis of FA. Moreover, intradermal tests carry a higher risk of adverse reactions than SPTs.
  • Balance of benefits and harms: Although intradermal testing may be more sensitive than skin prick testing for the diagnosis of IgE-mediated FA, there is no evidence to support such claims for protein-induced FA and insufficient evidence to support its routine use in diagnosing carbohydrate-induced FA. In addition, there is a greater risk of systemic adverse allergic reactions from intradermal tests compared with SPTs.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • Intradermal testing for FA does not provide increased sensitivity in detecting food protein-induced allergic reactions. There is suggestive but unconfirmed evidence to support its use in diagnosing a form of carbohydrate-induced IgE-mediated allergy that is a characteristic of some types of red meat allergy

Total serum IgE

  • Guideline 6: The EP recommends that the routine use of measuring total serum IgE should not be used to make a diagnosis of FA.
  • Rationale: Insufficient evidence exists to support the proposal that measurements of total serum IgE levels can be a sensitive and specific test for FA.
  • Balance of benefits and harms: Although an elevated total serum IgE level is frequently found in atopic individuals and some investigators suggest that it may be useful when interpreting allergen-specific IgE levels, the EP could find no studies to support such a claim. In addition, the sensitivity and specificity of this test compared with the outcome of oral food challenges is insufficient to warrant routine use in evaluating FA.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • Mehl et al looked at the predictive value of the ratio of sIgE to total IgE for the diagnosis of FA compared with the DBPCFC and concluded that the ratio offered no advantage over sIgE alone in diagnosing FA.

Allergen-specific serum IgE

  • Guideline 7: The EP recommends sIgE tests for identifying foods that potentially provoke IgE-mediated food-induced allergic reactions, but alone these tests are not diagnostic of FA.
  • Rationale: sIgE tests are useful for identifying foods potentially provoking IgE-mediated food-induced allergic reactions, and specified “cutoff” levels, defined as 95% predictive values, may be more predictive than SPTs of clinical reactivity in certain populations, but when used alone they are not diagnostic of FA.
  • Balance of benefits and harms: sIgE tests are very useful for detecting the presence of sIgE antibodies, which indicates the presence of allergic sensitization. Fluorescence-labeled antibody assays have comparable sensitivity to that of SPTs, and the absolute levels of sIgE antibodies may directly correlate with the likelihood of clinical reactivity when compared with oral food challenges for the identification of foods provoking IgE-mediated FA.
  • Quality of evidence: Moderate
  • Contribution of expert opinion: Significant
  • sIgE testing and skin prick testing both depend on the presence of allergen-specific antibodies. Because the former test measures sIgE in the serum and the latter reflects IgE bound to cutaneous mast cells, their results may not always correlate. Serum testing can be especially useful when SPTs cannot be done (for example, due to extensive dermatitis or dermatographism), or when antihistamines cannot be discontinued.
  • sIgE levels were originally measured using the radioallergosorbent test (RAST), but this test has been replaced by more sensitive fluorescence enzyme-labeled assays and the term RAST should be abandoned.
  • It is important to note that results from different laboratories or different assay systems may not be comparable. Wang et al examined 50 patients who were between 2 and 20 years of age and used 3 different systems (Phadia ImmunoCAP, Agilent Turbo-MP, and Siemens Immulite 2000) to assess for allergy to milk, egg, and peanut, as well as 3 aeroallergens. Each system used slightly different forms of the antigens (for example, skim milk vs freeze-dried milk vs whole milk). Of the 50 patients, 42 had diagnosed FA. Each system provided significantly different measurements of sIgE for the same serum samples. Thus, the predictive values associated with clinical evidence of allergy for ImmunoCAP cannot be applied to other test methods, for example, Turbo-MP and Immunlite.
  • The presence of sIgE reflects allergic sensitization and not necessarily clinical allergy. Several studies comparing the quantity of sIgE to oral food challenges have reported that the greater the levels of sIgE, the higher the probability that ingestion of the food will lead to an allergic reaction. However, the predictive values varied from one study to another. This inconsistency may be due to multiple factors, such as patients’ ages, duration of food allergen avoidance at the time of testing, selection of patients, and clinical disorders of patients being studied.
  • Undetectable sIgE levels occasionally occur in patients with IgE-mediated FA. Therefore, in cases where the history is highly suggestive, further evaluation (for example, physician-supervised oral food challenge) is necessary before telling a patient that he or she is not allergic to a suspected food and may ingest it.

Atopy patch test

  • Guideline 8: The EP suggests that the APT should not be used in the routine evaluation of non-contact FA.
  • Rationale: Insufficient evidence exists to support the use of the APT for the evaluation of FA.
  • Balance of benefits and harms: Although a number of studies have reported that the APT may be useful in the evaluation of FA in patients with AD and EoE, there is no agreement on the appropriate reagents, methods, or interpretation of these tests. When compared with oral food challenges, APTs show highly variable sensitivity and specificity among different studies.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • In general, a patch test is used to determine allergic sensitivity by applying small pads soaked with allergen to the unbroken skin. The APT is a specific type of patch test.121 The only difference between the APT and other patch tests is the antigen that is being tested. The APT uses allergens (for example, food allergens) that provoke only IgE-mediated reactions, whereas all other patch tests use antigens that typically provoke T cell-mediated reactions. All patch tests are performed the same way.
  • The APT is an investigational tool for diagnosing FA and is generally used to assess delayed, or non-IgE-mediated, reactions to an allergen. However, there are no standard reagents available, and no studies that specifically addressed the methodology of APTs met the criteria to be included in the RAND evidence report. Some studies reported that test material was applied directly to the skin for 48 hours and read at 72 hours following application, although most studies reported applying foods (fresh or from powders) in aluminum discs to the skin for 48 hours, with a final reading at 72 hours after application. The sensitivity and specificity of the test varied between studies and may have been affected by the presence of AD and the age of the patient. No studies compare the use of different food allergen preparations. Two large studies conclude that there is no significant clinical value in using APTs for diagnosing FA.

Use of skin prick tests, sIgE tests, and atopy patch tests in combination

  • Guideline 9: The EP suggests not using the combination of SPTs, sIgE tests, and APTs for the routine diagnosis of FA.
  • Rationale: No literature supports the proposal that the use of SPTs, sIgE tests, and APTs in combination for the evaluation of FA provides any significant advantage over the use of SPTs or sIgE tests alone.
  • Balance of benefits and harms: Combining the results of SPTs, sIgE tests, and APTs may provide higher positive and negative predictive values than any test alone, but use of all 3 tests is time consuming, inconvenient for the patient, and provides marginally improved positive and negative predictive values that may not be clinically relevant. However, a combination of 2 of these methods is sometimes more helpful for identifying foods likely to induce allergic reactions.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • A few studies show that various combinations of SPTs, sIgE tests, and APTs improved the sensitivity and specificity over the use of individual tests. However, the small number of studies that calculated the proportion of patients for whom 2 or more tests could obviate the need for a DBPCFC found these proportions to be quite small.

Food elimination diets

  • Guideline 10: The EP suggests that elimination of 1 or a few specific foods from the diet may be useful in the diagnosis of FA, especially in identifying foods responsible for some non-IgE-mediated food-induced allergic disorders, such as FPIES, AP, and Heiner syndrome, and some mixed IgE- and non-IgE-mediated food-induced allergic disorders, such as EoE.
  • Rationale: The use of an elimination diet in combination with a convincing history may be sufficient to diagnose FA in several food-induced allergic disorders, including FPIES, AP, and Heiner syndrome, and some mixed IgE- and non-IgE-mediated food-induced allergic disorders, such as EoE.
  • Balance of benefits and harms: In several non-IgE-mediated FA disorders and EoE, a suggestive medical history plus the elimination of the suspected food resulting in the resolution of symptoms provides evidence for the diagnosis of FA. In these situations, there are no known laboratory tests that are diagnostic of the causative food, and the oral food challenge, while a potentially useful diagnostic test, may provoke significant morbidity. Thus, many health care professionals base the initial diagnosis on history and clearing of symptoms while on the elimination diet, and reserve the oral food challenge for evaluating the eventual resolution of the disorder (ie, development of tolerance).
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • RAND found no studies meeting the inclusion criteria to support the diagnostic value of using dietary elimination trials or of food/symptoms diaries for the diagnosis of FA. However, given the morbidity of oral food challenges in some non-IgE-mediated food-induced allergic disorders, some investigators believe that a convincing history plus clearing of symptoms with the initiation of an elimination diet for a particular food is sufficient to make the diagnosis of FA. However, prolonged elimination diets that omit multiple foods have been reported to induce severe malnutrition;126, 127, 128 therefore, confirmatory diagnostic studies must be performed in such cases to confirm the diagnosis of FA.

Oral food challenges

  • Guideline 11: The EP recommends using oral food challenges for diagnosing FA. The DBPCFC is the gold standard. However, a single-blind or an open-food challenge may be considered diagnostic under certain circumstances: if either of these challenges elicits no symptoms (ie, the challenge is negative), then FA can be ruled out; but when either challenge elicits objective symptoms (ie, the challenge is positive) and those objective symptoms correlate with medical history and are supported by laboratory tests, then a diagnosis of FA is supported.
  • Rationale: DBPCFC is the most specific test for diagnosing FA. However, due to the expense and inconvenience of DBPCFCs, single-blind and open-food challenges may be used in the clinical setting.
  • Balance of benefits and harms: The DBPCFC markedly reduces potential bias of patients and supervising health care professionals that may interfere with the appropriate interpretation of oral food challenges, and corresponds most closely to the natural ingestion of food. Other diagnostic tests lack specificity and may lead to the unnecessary exclusion of foods from patients’ diets. However, the DBPCFC is time consuming, expensive, and, like any form of oral food challenge, subjects the patient to potential severe allergic reactions. Single-blind and open-food challenges are frequently used to screen patients for FA. When negative, they may be considered diagnostic in ruling out FA, and when positive (ie, when “immediate” objective allergic symptoms are elicited), they may be considered diagnostic in patients who have a supportive medical history and laboratory data.
  • Quality of evidence: High
  • Contribution of expert opinion: Moderate
  • Because of the inherent risk, an oral food challenge must be conducted at a medical facility that has onsite medical supervision and appropriate medicines and devices on hand.
  • A positive SPT or sIgE test result is indicative of allergic sensitization, but these findings alone may or may not be clinically relevant. Most investigators in the field agree that verification of clinical reactivity requires well-designed oral food challenge testing.
  • Prior to initiating an oral food challenge, suspected foods are eliminated from the diet for 2 to 8 weeks, depending on the type of food-induced allergic reaction being examined (for example, urticaria vs EoE). All foods in question must be strictly avoided simultaneously. An infant’s diet can be limited to a hypoallergenic formula. For exclusively breast-fed infants, either the suspected food is eliminated from the mother’s diet or the baby is fed a hypoallergenic formula until the allergic food is identified.
  • After documenting significant improvement on dietary elimination, the challenge test is carried out while the patient is on minimal or no symptomatic medication. The test should be designed and performed under medical supervision to document the dose that provokes the reaction and to administer symptomatic treatment, which may require management of anaphylaxis (section 6), and the medical personnel should have experience in carrying out such challenges. Oral food challenge begins with a low dose (intended to be lower than a dose that can induce a reaction). While monitoring for any allergic symptoms, the dose is gradually increased, until a cumulative dose at least equivalent to a standard portion for age is consumed. The challenge may be carried out in an open fashion in infants, but in older children, single-blind food challenges or DBPCFCs may be necessary to minimize patient and physician bias.
  • Using DBPCFC, several studies have shown that only about one third of the suspected foods are found to be truly allergic. In addition to verifying FA, challenge testing prevents unnecessary dietary avoidance and enhances compliance with the elimination diet. Nevertheless, because of the risk of a severe reaction, intentional challenge should be avoided in patients who have recently experienced a life-threatening reaction to a particular food, particularly if it occurred more than once. In the case of post-prandial exercise-induced reactions, food challenge should be followed by exercise
  • There is currently no internationally accepted, standardized protocol for performing and interpreting DBPCFCs, although reviews outlining benefits and deficiencies have been published.

Nonstandardized and unproven procedures

  • Guideline 12: The EP recommends notusing any of the following nonstandardized tests for the routine evaluation of IgE-mediated FA: Basophil histamine release/activation, Lymphocyte stimulation, Facial thermography. Gastric juice analysis, Endoscopic allergen provocation, Hair analysis, Applied kinesiolog, Provocation neutralization, Allergen-specific IgG4 Cytotoxicity assays, Electrodermal test (Vega) andMediator release assay (LEAP diet)
  • Rationale: There is a lack of evidence demonstrating that any of these nonstandardized tests has any value in the diagnosis of FA. However, although basophil histamine release/activation is not a routine diagnostic test for IgE-mediated FA, it is commonly used as a research tool.
  • Balance of benefits and harms: The utility of these tests has not been validated for the diagnosis of FA and may result in false positive or false negative diagnoses, leading to unnecessary dietary restrictions or delaying the appropriate diagnostic workup, respectively.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant

Diagnosis of non-IgE-mediated immunologic adverse reactions to food

The diagnosis of non-IgE-mediated FA can be challenging. Prior to a diagnostic workup, it may be difficult to distinguish an IgE-mediated allergy from a non-IgE-mediated allergy based on medical history and physical examination alone. Some distinct non-IgE-mediated conditions are associated with FA. T cells have been shown to play a central role in celiac disease. Studies have also shown that T cells may mediate the pathogenesis of some other non-IgE-mediated adverse reactions to food. A number of diagnostic tools have been suggested for use in diagnosing non-IgE-mediated reactions, including DBPCFC, contact dermatitis patch testing, APT, intradermal testing, lymphocyte activation assays, food-specific IgG testing, and endoscopic biopsy.

Specific examples of non-IgE-mediated adverse reactions to foods include:

•Eosinophilic GI diseases (EGIDs)
•Food protein-induced enterocolitis syndrome (FPIES)
•Food protein-induced allergic proctocolitis (AP)
•Food protein-induced enteropathy syndrome
•Allergic contact dermatitis (ACD)
•Systemic contact dermatitis
•Heiner syndrome (see section 2.1.3)

Eosinophilic gastrointestinal diseases

  • Guideline 13: The EP suggests that SPTs, sIgE tests, and APTs may be considered to help identify foods that are associated with EoE, but these tests alone are not sufficient to make the diagnosis of FA. The role of these tests in the diagnosis of other EGIDs has not been established.
  • Rationale: SPTs, sIgE tests, and APTs alone are insufficient to establish a causal role for FA in EoE, but they may be useful in identifying foods that should be investigated further with other diagnostic tests, such as dietary elimination, oral food challenge, and endoscopy and esophageal biopsy.
  • Balance of benefits and harms: Some studies suggest that SPTs, sIgE tests, and APTs may be of value in identifying foods that cause symptoms of EoE. However, the utility of these tests has not been validated for the diagnosis of FA in EoE or other EGIDs and may result in false positive or false negative diagnoses.
  • Quality of evidence: Low
  • Contribution of expert opinion: Significant
  • EGIDs are a diverse group of intestinal diseases that require endoscopic analysis with mucosal biopsy to make the diagnosis. The diagnosis of EoE, which is a common form of EGID, is defined by an esophageal biopsy with the finding of >15-20 eosinophils per high power field. A method for demonstrating that FA is relevant to the course of EoE is resolution of symptoms and esophageal eosinophilia following dietary elimination, and recurrence of esophageal eosinophilia with reintroduction of the suspected food.17
  • Because food allergens are thought to play a large role in the pathogenesis of these diseases, sIgE tests and SPTs are used to identify potentially relevant foods and design an optimal elimination diet. However, little evidence supports the use of these tests in predicting the severity of EGID symptoms, and no studies have systematically assessed the positive and negative predictive values of SPT or sIgE results in evaluating the potential relevant role of FA in EoE. Results from 1 study suggest some benefit of APT in identifying suspect food allergens, but this has not been confirmed in other studies.

Food protein-induced enterocolitis syndrome

  • Guideline 14: The EP recommends using the medical history and oral food challenge to establish a diagnosis of FPIES. However, when history indicates that infants or children have experienced hypotensive episodes or multiple reactions to the same food, a diagnosis may be based on a convincing history and absence of symptoms when the causative food is eliminated from the diet.
  • Rationale: FPIES is diagnosed based on a supportive medical history, resolution of symptoms with the elimination of the causative food, and, in many cases, provocation of symptoms following an open or single-blind oral food challenge.
  • Balance of benefits and harms: There are no laboratory studies with demonstrated specificity and sensitivity to diagnose FPIES, so an oral food challenge is necessary to establish the diagnosis. Although the oral food challenge may induce significant symptoms, there are no alternative methods with adequate predictability to diagnose FPIES. However, when the history is very compelling (for example, 2 or more reactions with classic symptoms to the same food in a 6-month period and elimination of symptoms when the causative food is removed from the diet), an oral food challenge may not be necessary to make the diagnosis. Because this disorder often lasts only a few years, however, subsequent oral food challenge is warranted to determine when FPIES has resolved and the food elimination diet can be terminated.
  • Quality of evidence: High
  • Contribution of expert opinion: Moderate
  • FPIES is a severe systemic response to food protein that typically occurs 1 to 4 hours after the ingestion of the causative food and frequently develops in the first few years of life. FPIES can manifest in young infants who frequently are breast-fed and presents as blood-streaked or hemoccult-positive stools in an infant who otherwise appears healthy. Symptoms include vomiting, diarrhea, acidosis, and in some cases shock. Laboratory studies consistent with this diagnosis include an elevated white blood cell count with a left shift and elevated platelet count.
  • Since FPIES occurs when the infant’s diet is quite limited, history is often helpful in identifying food triggers. Because FPIES is a non-IgE-mediated disorder, sIgE tests and SPTs are typically negative. Endoscopy may reveal a mixed eosinophilic and neutrophilic infiltrate but is not required to make the diagnosis. Young infants who develop FPIES in response to one formula or food are at greater risk of developing allergic reactions to other whole-protein formulas. Therefore, hypoallergenic formulas are recommended. Because hypotension may develop in up to 15% of cases, children should be challenged in a setting where intravenous hydration is readily available.

Food protein-induced allergic proctocolitis

  • Guideline 15: The EP recommends using the medical history, resolution of symptoms when the causative food is eliminated from the diet, and recurrence of symptoms following an oral food challenge to diagnose AP.
  • Rationale: The evidence supports the conclusion that food protein-induced AP can be diagnosed based on a supportive medical history, resolution of symptoms with the elimination of the causative food, and recurrence of symptoms following an oral food challenge.
  • Balance of benefits and harms: Because there are no laboratory studies with sufficient specificity and sensitivity to diagnose food protein-induced AP, an oral food challenge is necessary to establish the diagnosis. Although the food challenge may induce blood in the stools, symptoms of AP are generally benign, and there are no alternative methods with adequate predictability to diagnose AP. In cases with a classic history of AP, a normal physical examination and resolution of symptoms following elimination of the causative food leads many investigators to believe that an oral food challenge is not required to establish the diagnosis. Since this disorder often lasts only 1 to 2 years, repeated challenges are warranted to determine when food elimination diets can be terminated.
  • Quality of evidence: Moderate
  • Contribution of expert opinion: Significant
  • AP is a common transient disease of infancy, typically resolving in the first 1 to 2 years of life, that manifests itself as the passage of mucoid, blood-streaked stools in an otherwise healthy infant. AP also can manifest as chronic emesis, diarrhea, and failure to thrive. Upon re-exposure to the offending food after a period of elimination, a subacute syndrome can present with repetitive emesis and dehydration. Typically AP is associated with the ingestion of cow’s milk, soy milk, or human breast milk during infancy. Reports also exist of adults experiencing crampy abdominal pain, severe vomiting, light-headedness, and lethargy 2 to 3 hours following the ingestion of crustacean shellfish. Because AP is a non-IgE-mediated FA, sIgE and SPT results are typically negative. Although colonoscopy and biopsy are not generally necessary to make the diagnosis, they will reveal lesions that are confined to the large bowel and consist of mucosal edema with infiltration of eosinophils in the epithelium and lamina propria. In severe lesions with crypt destruction, polymorphonuclear leukocytes are also prominent. A recent study found that about one third of suspected infants had no evidence of eosinophils on biopsy, and AP resolved without a change in breast-feeding or formula.

Food protein-induced enteropathy syndrome

Food protein-induced enteropathy syndrome is an uncommon disorder that presents in young infants as chronic diarrhea (steatorrhea in up to 80% of cases), weight loss, and growth failure. Symptoms are similar to those observed in patients with celiac disease, except that they appear in young infants. The disorder is characterized by generalized malabsorption (of fat, carbohydrates, and other nutrients), thought to be due to changes in the structure of the intestinal mucosa. It is most often due to milk allergy,157 but also has been reported due to an allergy to soy, chicken, rice, and fish. Moderate anemia, hypoproteinemia, and deficiency of the vitamin K factors may occur. Diagnosis is based on the clinical symptoms, resolution with allergen elimination, and recurrence of symptoms following an oral food challenge. Treatment consists of strict allergen elimination from the diet. Virtually all affected patients “outgrow” their symptoms by 2 to 3 years of age, and therefore follow-up oral food challenges are recommended to determine when allergen elimination diets can be terminated.

Allergic contact dermatitis

  • Guideline 16: The EP recommends using the medical history, including the absence of symptoms while the causative food is avoided, and positive patch tests to diagnose ACD.
  • Rationale: There are a limited number of well-controlled studies demonstrating the utility of these methods in diagnosing ACD. However, the concept that patch testing can be useful in establishing the diagnosis of ACD is based on both the underlying immunologic mechanism involved in the disease and observations from general medical practice.
  • Balance of benefits and harms: Traditionally, patch testing has been used to support history in diagnosing ACD. Although there are insufficient well-controlled studies to demonstrate the benefits of these methods in diagnosing ACD, the concept of patch testing largely fits with the immunopathogenic mechanism involved. The harm of avoiding contact with the food identified by this method appears minimal.
  • Quality of evidence: Moderate
  • Contribution of expert opinion: Significant
  • ACD is a cell-mediated allergic reaction and may be triggered by foods or contaminants in foods. The immediate reactions in ACD may be initiated by contact with chemical moieties in the food, such as oleoresins in fruits and vegetables or spices. Examples include garlic causing contact dermatitis of the hands, mango causing perioral dermatitis, or raw chestnut causing hand and perianal dermatitis.27 A detailed medical history will aid in the diagnosis of ACD. Patch testing may be performed with standardized contact allergens or suspected allergens (ie, food allergens) applied to a healthy area of the skin, with eczematous reactions assessed 48 to 72 hours later.28 Positive reactions must be distinguished from simple irritant reactions. Furthermore, positive tests are a sign of sensitization to the allergen, but the clinical relevance of such sensitization needs to be assessed in the context of other clinical signs.

Reference :

  • Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol. Feb 2010;125(2 Suppl 2):S116-25.
  • Scott H. Sichererand Hugh A. Sampson. Food Allergy: Recent Advances in Pathophysiology and Treatment. Annual Review of Medicine Vol. 60: 261-277 (Volume publication date February 2009)
  • Sampson H (2004). “Update on food allergy”. J Allergy Clin Immunol 113 (5): 805–819. http://www.jacionline.org/article/PIIS0091674904011455/fulltext.
  • Julie Wang and Hugh A Sampson. Food allergy: recent advances in pathophysiology and treatment. Allergy Asthma Immunol Res. 2009 October; 1(1): 19–29.
  • Lemon-Mule H, Sampson HA, Sicherer SH, Shreffler WG, Noone S, Nowak-Wegrzyn A. Immunologic changes in children with egg allergy ingesting extensively heated egg. J Allergy Clin Immunol. 2008;122:977–983
  • Shreffler WG, Castro RR, Kucuk ZY, Charlop-Powers Z, Grishina G, Yoo S, et al. The major glycoprotein allergen from Arachis hypogaea, Ara h 1, is a ligand of dendritic cell-specific ICAM-grabbing nonintegrin and acts as a Th2 adjuvant in vitro. J Immunol. 2006;177:3677–3685
  • Meyer S, van Liempt E, Imberty A, van Kooyk Y, Geyer H, Geyer R, et al. DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. J Biol Chem. 2005;280:37349–37359
  • Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2009;123:426–433
  • Anna Nowak-Węgrzyn, Hugh A. Sampson. Future therapies for food allergies. Journal of Allergy and Clinical Immunology March 2011 Vol. 127, Issue 3, Pages 558-573
  • Scott H. Sicherer, Hugh A. Sampson. Journal of Allergy and Clinical Immunology February 2010 Vol. 125, Issue 2, Supplement 2, Pages S116-S125
  • Stephan Steckelbroeck, Barbara K. Ballmer-Weber, Stefan Vieths. Potential, pitfalls, and prospects of food allergy diagnostics with recombinant allergens or synthetic sequential epitopes. Journal of Allergy and Clinical Immunology June 2008 Vol. 121, Issue 6, Pages 1323-1330
  • A. Wesley Burks, Mimi Tang, Scott Sicherer, Antonella Muraro, et al. ICON: Food allergy. Journal of Allergy and Clinical Immunology 24 February 2012
  • Report of the NIAID-Sponsored Expert Panel, NIAID-Sponsored Expert Panel. Guidelines for the Diagnosis and Management of Food Allergy in the United States: Practice guideline. December 2010. Journal of Allergy and Clinical Immunology Vol. 126, Issue 6, Supplement, Pages S1-S58

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